Ketone Bodies and Ketogenesis

Ketone Bodies

• Ketone bodies are partially oxidized fatty acids.
• Three types are produced by the liver:
  • Acetoacetate ("acetoacetic acid")
  • β-Hydroxybutyric acid
  • Acetone
• Important energy source during prolonged fasting and starvation, particularly for tissues like the brain, but not the liver (which lacks necessary enzymes).

Ketogenesis

• Definition: Synthesis of ketone bodies from active acetate derived from fatty acid oxidation and ketogenic amino acids.
• Location:
  • Intracellular: Mitochondria
  • Organ: Liver
• Steps:
  • Acetoacetate is formed first, then the other two ketone bodies are derived from it.
  • Acetoacetyl CoA formation:
    • Byproducts of β-oxidation of fatty acids with even numbers.
    • By the condensation of two acetyl CoA molecules.
  • Conversion of acetoacetyl CoA to acetoacetate: Deacylation of acetoacetyl CoA.
  • Formation of β-Hydroxybutyric acid: From acetoacetate by β-hydroxybutyric acid dehydrogenase, using NADH+H.
  • Formation of acetone: Lost in expired air and urine; characteristic odor in uncontrolled diabetes.

Ketogenesis Steps Summary

• Fatty acids undergo β-oxidation; excess acetyl CoA is generated.
• Acetyl CoA produces acetoacetyl CoA.
• Acetoacetyl CoA forms acetoacetate (the initial ketone).
• Acetoacetate converts to β-hydroxybutyrate and then acetone.

Regulation of Ketogenesis

• Conditions associated with increased ketogenesis:
  • Starvation and fasting
  • Diabetes
  • High-fat diet
  • Low-carbohydrate diet
• Factors regulating ketogenesis:
  • Rate of free fatty acids arriving at the liver
  • Hormonal regulation
  • Amount of energy in the cell

Ketogenesis Regulation After Meals

• Insulin secretion inhibits lipolysis
• Reduced free fatty acids in the plasma
• Reduced uptake of free fatty acids by the liver
• Reduced β-oxidation
• Reduced acetyl CoA precursor
• Reduced ketone body production

Ketogenesis Regulation During Starvation

• Anti-insulin hormone (glucagon) stimulates lipolysis
• Elevated free fatty acids in the plasma
• Increased uptake of free fatty acids by the liver
• Increased β-oxidation
• Increased acetyl CoA precursor
• Increased ketone body production

Ketolysis (Ketone Body Oxidation)

• Complete oxidation of ketone bodies into H₂O and CO₂.
• Location: Extrahepatic tissues (not in the liver, which lacks enzymes).
• Steps:
  • Acetone is lost in urine and expired air.
  • β-hydroxybutyric acid is converted into acetoacetate, with NADH+H production.

Acetoacetate Activation

• Acetoacetate activation in extrahepatic tissues occurs via two pathways.
• Major pathway: Thiophorase transfers CoA from succinyl CoA to acetoacetate, creating acetoacetyl CoA.
• Minor pathway: Acetoacetyl CoA synthetase activates acetoacetate in the presence of ATP and CoA, also creating acetoacetylCoA.

Bioenergetics of Ketolysis

• Oxidation of one β-hydroxybutyric acid molecule produces:
  • 1 NADH = 2.5 ATP
  • 2 Acetyl CoA = 20 ATP
  • 1 ATP loss
  • Net energy = 22.5 -1 = 21.5 ATP

Ketosis

• Definition: When the rate of ketogenesis exceeds the oxidative capacity of extrahepatic tissues to use ketone bodies, leading to elevated ketone levels in the blood (ketonemia) and urine (ketonuria).

Causes of Ketosis

• Pathological causes:
  • Phlorhizin poisoning
  • Diabetes mellitus
  • Renal glucosuria
• Non-pathological causes:
  • Starvation
  • Carbohydrate-poor diet
  • High-fat diet
  • Excessive exercise

Ketoacidosis

• Definition: A type of metabolic acidosis that arises from ketosis.
• Mechanism: Increased ketone bodies (weak acids) are neutralized by blood buffers (primarily bicarbonate), decreasing blood pH (acidosis).
• Effects:
  • Acidosis can cause potassium ion transfer from intracellular to extracellular fluid, leading to hyperkalemia.
  • Dizziness and loss of concentration
  • Severe cases may result in coma.

Explore the fascinating world of ketone bodies and their synthesis through ketogenesis. This quiz covers their types, production in the liver, and significance during fasting. Test your understanding of the metabolic pathways associated with fatty acids and energy utilization.